PMID: 14624143

Issn Print: 0957-9672

Publication Date: 2003/12/01


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Therapy and clinical trials: ezetimibe

Ishwarlal Jialal; Tissa Kappagoda

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Ezetimibe is the first in a new class of lipid lowering compounds that selectively inhibits the intestinal absorption of dietary and biliary cholesterol and related phytosterols. Ezetimibe localizes and appears to act at the brush border of the small intestine and inhibits cholesterol absorption resulting in the decrease in the delivery of intestinal cholesterol to the liver. This translates to a reduction in hepatic cholesterol stores thereby promoting the synthesis of LDL receptors with a subsequent reduction in serum LDL cholesterol [1••]. In addition to inhibiting cholesterol absorption, ezetimibe also inhibits net phytosterol absorption. Its mechanism of action is different from that of other intestinal-acting lipid altering agents such as resins and stanol esters. With respect to its pharmacology, ezetimibe undergoes rapid and extensive glucuronidation in the intestinal wall and the liver. The elimination half-life for ezetimibe and ezetimibe glucuronide is approximately 22 h. The pharmacokinetics of the compound do not appear to depend on sex, age, renal or hepatic function. It was shown that at a dose of 10 mg a day the drug reduced a fractional cholesterol absorption by 54% compared with placebo in 18 patients with mild to moderate hypercholesterolemia [2••] This effect was accompanied by a decrease in LDL cholesterol of approximately 20% and a compensatory increase of 89% in cholesterol synthesis versus placebo. It also reduced plasma concentrations of non-cholesterol sterols, sitosterol and campesterol. Pharmacokinetic studies to date with statins, fibrates, and ezetimibe have not revealed any significant interactions. Moreover ezetimibe has no effect on the activity of drug metabolizing enzymes such as cytochrome P450 or N-acetyltransferase. Thus the pharmacokinetic interaction potency seems to be low as illustrated by the lack of clinical significant interactions with warfarin, glipizide, digoxin, oral contraceptives, antacids, or cimetidine. Nonetheless cholestyramine was shown to reduce the systemic plasma concentration of ezetimibe by about 55%.
The advent of this new drug clearly will have major implications for getting patients to target according to the adult treatment panel guidelines either as monotherapy or as combination therapy. To date in studies using monotherapy in 892 patients with primary hypercholesterolemia, ezetimibe compared with placebo was shown to decrease direct LDL cholesterol by 17% [3••]. The reduction in LDL cholesterol occurred early (at 2 weeks) and persisted over 12 weeks. The effect of ezetimibe on LDL cholesterol was consistent among subgroups analyzed regardless of risk factor status, race, sex or baseline lipid profile. Therapy was also associated with a significant reduction in apolipoprotein B, triglycerides and an increase in HDL cholesterol. Knopp et al.[4•] conducted a randomized double blind placebo controlled parallel group study evaluating the safety and efficacy of ezetimibe at 10 mg per day in patients with primary hypercholesterolemia. Following dietary stabilization and a washout period, 827 patients with baseline LDL cholesterol ranging from 130 to 250 mg/dl and triglycerides below 350 mg/dl were randomized to receive ezetimibe 10 mg per day or placebo orally once daily in the morning for 12 weeks. The drug treatment reduced direct LDL cholesterol by 18% from baseline to endpoint. The response was generally consistent across all subgroups analyzed. Ezetimibe also significantly improved levels of plasma total cholesterol, apolipoprotein B, HDL2 cholesterol and lipoprotein(a), and elicited a trend toward lower triglyceride levels. It did not alter the serum concentrations of lipid-soluble vitamins or significantly affect baseline or stimulated cortisol production. The compound was well tolerated, with a safety profile similar to that of placebo. Thus, it is clear that ezetimibe monotherapy is a very safe and effective way of lowering LDL cholesterol and in addition has favorable effects on HDL cholesterol and triglycerides.
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